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WO1999009964A2 - Pharmaceutical composition containing clindamycin and clotrimazol for treating vaginal infections - Google Patents

Pharmaceutical composition containing clindamycin and clotrimazol for treating vaginal infections Download PDF

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Publication number
WO1999009964A2
WO1999009964A2 PCT/EP1998/005454 EP9805454W WO9909964A2 WO 1999009964 A2 WO1999009964 A2 WO 1999009964A2 EP 9805454 W EP9805454 W EP 9805454W WO 9909964 A2 WO9909964 A2 WO 9909964A2
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WO
WIPO (PCT)
Prior art keywords
clindamycin
clotrimazole
pharmaceutical composition
layer
vaginal
Prior art date
Application number
PCT/EP1998/005454
Other languages
German (de)
French (fr)
Other versions
WO1999009964A3 (en
Inventor
Dan-Gabriel Vulpescu
Brigitte Freudensprung
Original Assignee
Hexal Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hexal Ag filed Critical Hexal Ag
Priority to DE59813162T priority Critical patent/DE59813162D1/en
Priority to JP2000507355A priority patent/JP2001513550A/en
Priority to US09/486,348 priority patent/US6537970B1/en
Priority to EP98948878A priority patent/EP1009414B1/en
Priority to AU95343/98A priority patent/AU9534398A/en
Priority to AT98948878T priority patent/ATE308328T1/en
Publication of WO1999009964A2 publication Critical patent/WO1999009964A2/en
Publication of WO1999009964A3 publication Critical patent/WO1999009964A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina

Definitions

  • the invention relates to a new pharmaceutical composition containing a combination of clindamycin and clotrimazole for vaginal use in bacterial infections, fungal or mixed infections of the vagina.
  • Conventional therapies for the treatment of bacterial vaginal infections e.g. Bacterial vaginosis, which is caused by the interaction of Gardnerella vaginalis and anaerobic bacteria, provides treatments with chemotherapeutic agents with an effect on anaerobes and protozoa, such as: metronidazole or tinidazole, or treatment with an antibiotic such as amoxicillin or clindamycin. Treatment is either oral or by local vaginal application.
  • Oral therapy with one of these active substances has considerable disadvantages, e.g. the occurrence of significant side effects or undesirable interactions with other drugs.
  • Metronidazole is also suspected to have carcinogenic potential.
  • Local therapy is definitely preferable to systemic therapy to avoid systemic stress on the body.
  • a major disadvantage of the above-described therapies with an antibiotic or a chemotherapeutic agent is that a secondary infection, e.g. B. vaginal candidiasis or a mixed infection can occur within the following month, which requires re-treatment with another drug. A very precise and time-consuming diagnosis is then necessary to determine what type of colpitis is present so that medication can be treated correctly.
  • a secondary infection e.g. B. vaginal candidiasis or a mixed infection
  • vaginal candidiasis a fungal infection that requires treatment with an antifungal such as e.g. Clotrimazole required.
  • Clotrimazole is a local antifungal drug with a broad spectrum of activity, which includes many human-pathogenic fungi. In gynecology, clotrimazole is primarily used as a monotherapy for the treatment of vulvovaginal infections caused by yeast or shoots. With local therapy with clotrimazole, doses of 500 mg are provided for single use. Treatment therapies lasting several days are carried out with doses of approx. 100-200 mg of clotrimazole.
  • clotrimazole has a low antibacterial effect.
  • the object of the invention is to provide a pharmaceutical composition for the treatment of vaginal diseases in which the side effects are reduced and with which the treatment is simpler and more efficient.
  • the combination shows a clear one synergistic effect. While according to the prior art clindamycin is to be administered in local therapy in dose amounts of 100-200 mg per day in order to achieve complete healing of the disease, the clindamycin dose in the new combination can be reduced to 10-80 mg, preferably to 20-50 mg can be reduced. Depending on the severity of the disease, dose amounts of 10-80 mg, preferably 20-50 mg clindamycin in combination with 50-150 mg, preferably 50-100 mg clotrimazole are administered.
  • the new pharmaceutical composition is for local use in the treatment of vaginal infections.
  • the pharmaceutical composition can contain pharmaceutically acceptable carriers or excipients.
  • Preferred dosage forms are vaginal suppositories, vaginal tablets, vaginal ovula, vaginal rings or semi-solid vaginal preparations such as ointment, cream or gel.
  • starch e.g. Corn starch, rice starch, potato starch, wheat starch, milk sugar (lactose), glucose, sucrose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, stearic acid, talc, polyvinylpyrrolidone (linear and crosslinked), sodium chloride, polyethylene glycol, hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, hydroxypropylcellulose, cellulose Mannitol, sodium carboxymethyl starch, sodium carbonate, sodium bicarbonate, calcium carbonate, sodium carboxymethyl cellulose (linear and cross-linked) and magnesium stearate.
  • starch e.g. Corn starch, rice starch, potato starch, wheat starch, milk sugar (lactose), glucose, sucrose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, stearic acid, talc, polyvinylpyrrolidone (linear and crosslinked), sodium chloride, polyethylene glycol, hydroxypropyl
  • auxiliaries for creams are understood here to mean the following: sorbitan monostearate, polysorbate 60, cetyl palmitate, paraffin, cetylstearyl alcohol, benzyl alcohol, silicon dioxide, triacetin, isopropyl monostearate, polyethylene glycol, Glycerol monostearate, polyacrylic acid, sodium hydroxide, docusate sodium, dimethicone, triglycerides, octyldecanol and octyldodecanol.
  • the usual excipients for ovules are understood here to mean the following: gelatin, glycerol, polyethylene glycol, hard fat, cetostearyl alcohol polyethylene glycol ether, sodium dodecyl sulfate, glycerol (mono, di, tri) fatty acid ester (C 12 -C 18) polyethylene glycol dodecyl ether mixture, paraffin, ethyl 4 -hydroxybenzoate, propyl-4-hydroxybenzoate and petroleum jelly.
  • the vaginal tablets can be in the form of single-layer, two-layer or three-layer tablets or as tablets with effervescent.
  • the active components of the new composition are present in concentrations of 10-80 mg clindamycin and 50-150 mg clotrimazole, preferably 20-50 mg clindamycin and 50-100 mg clotrimazole, in particular in 20 mg clindamycin and 100 mg clotrimazole per application or dose unit .
  • the new combination can be used to treat a wide range of vaginal diseases.
  • the most common colpitids, candida colpitis (fungal infection) and bacterial vaginosis (mixed bacterial infection) can be successfully treated.
  • the combination according to the invention allows the treatment of so-called mixed infections caused by bacteria and fungi.
  • both pathogens are combated simultaneously.
  • the most common secondary infection is candidiasis.
  • the Combination according to the invention in the treatment can prevent such secondary infections. This eliminates the need for further treatment, which on the one hand is very unpleasant for the patient and is associated with an extended treatment duration, and on the other hand, the combination therapy can significantly reduce the financial outlay from a health policy point of view.
  • Clindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg
  • HPC Hydroxypropyl cellulose
  • Microcrystalline cellulose (Avicel PH 102) 128.0 mg
  • Clotrimazole, clindamycin HCl, lactose, part of the corn starch, HPC, calcium lactate and lactic acid are granulated in a fluidized bed granulator.
  • the granules obtained and the remaining part of the corn starch, Kollidon, microcrystalline cellulose, magnesium stearate and Aerosil are passed through a forced sieve (1.25 mm) and homogenized in a container mixer.
  • the mixture obtained is compressed to tablets on a rotary tablet machine.
  • Example 2 Example 2:
  • Clindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg
  • Microcrystalline cellulose (Avicel PH 102) 128.0 mg
  • a tablet is produced in analogy to Example 1 with the ingredients specified above.
  • Clindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg
  • Microcrystalline cellulose (Avicel PH 102) 384.5 mg
  • Clotrimazole, clindamycin HCl, lactose, part of the corn starch, part of the microcrystalline cellulose, HPC, calcium lactate and lactic acid are granulated in a fluidized bed granulator.
  • the granules obtained and the remaining part of the corn starch and the microcrystalline cellulose, Kollidon, magnesium stearate and Aerosil are passed through a forced sieve (1.25 mm) and homogenized in a container mixer.
  • the mixture obtained is compressed to tablets on a rotary tablet machine.
  • Clindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg
  • Microcrystalline cellulose (Avicel PH 102) 128.0 mg 128.0 mg
  • Aerosil 200 7.0 mg 7.7 mg
  • Example 5 the above-mentioned constituents are used to produce granules for the first layer and, on the other hand, granules for the second layer analogously to Example 1 and pressed into a two-layer tablet.
  • Example 5 the above-mentioned constituents are used to produce granules for the first layer and, on the other hand, granules for the second layer analogously to Example 1 and pressed into a two-layer tablet.
  • Clindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg
  • Microcrystalline cellulose (Avicel PH 102) 128.0 mg 128.0 mg
  • Aerosil 200 7.0 mg 7.7 mg
  • a tablet is produced in analogy to Example 4 with the ingredients specified above.
  • Clindamycin HCL (equivalent to 10 mg clindamycin) 11.4 mg
  • Microcrystalline cellulose (Avicel PH 102) 128.0 mg Kollidon CL 12.0 mg
  • a tablet is produced in analogy to Example 1 with the ingredients specified above.
  • Clindamycin HCL (equivalent to 30 mg clindamycin) 34.1 mg
  • Microcrystalline cellulose (Avicel PH 102) 140.0 mg 135.0 mg
  • Aerosil 200 9.0 mg 9.0 mg
  • Example 8 A tablet is produced in analogy to Example 4 with the ingredients specified above.
  • Example 8 A tablet is produced in analogy to Example 4 with the ingredients specified above.
  • Clindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg
  • Microcrystalline cellulose (Avicel PH 102) 128.0 mg 128.0 mg
  • Aerosil 200 7.0 mg 7.7 mg
  • the second layer represents an intermediate layer which is located between the first and third layers.
  • Clindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg
  • Microcrystalline cellulose (Avicel PH 102) 128.0 mg 60.0 mg
  • Aerosil 200 7.0 mg 1.6 mg
  • the first layer is granulated analogously to Example 1 with the constituents specified above.
  • the clindamycin-containing layer is not granulated, but is pressed directly with the granulate of the first layer into a two-layer tablet.
  • Clindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg
  • Microcrystalline cellulose (Avicel PH 102) 120.0 mg Citric acid 50.0 mg
  • Clotrimazole, clindamycin HCl, lactose, corn starch, HPC, calcium lactate and lactic acid are granulated in a fluidized bed granulator.
  • the granules obtained are mixed with the other effervescent and / or disintegrating components, as well as with microcrystalline cellulose, magnesium stearate and Aerosil, and compressed into tablets.
  • One application unit is 5 grams. This contains 100 mg clotrimazole and 20 mg clindamycin.
  • Clindamycin HCl (equivalent to 4 mg clindamycin) 4.54 mg
  • Polysorbate 60 (Tween 60) 15.0 mg
  • Clindamycin HCI (equivalent to 20 mg clindamycin) 22.7 mg
  • Clindamycin HCI (equivalent to 20 mg clindamycin) 22.7 mg
  • Clindamycin HCI (equivalent to 20 mg clindamycin) 22.7 mg
  • Clindamycin HCI (equivalent to 20 mg clindamycin) 22.7 mg
  • the pharmaceutical composition according to the invention was used in a study in 25 patients.
  • a bacterial mixed infection was found in 20 cases, in 3 cases a mixed infection caused by bacteria and fungi and in 2 cases a pure fungal infection.
  • vaginal ovula which contained 20 mg clindamycin and 100 mg clotrimazole
  • the infection was completely healed in 23 patients. Furthermore, no secondary infections were found.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Gynecology & Obstetrics (AREA)
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Abstract

The invention relates to a new pharmaceutical composition containing clindamycin and clotrimazol used for the treatment of vaginal infections.

Description

Neue pharmazeutische Zusammensetzung New pharmaceutical composition

Die Erfindung betrifft eine neue pharmazeutische Zusammensetzung enthaltend eine Kombination aus Clindamycin und Clotrimazol zur vaginalen Anwendung bei bakteriellen Infektionen, Pilz- oder Mischinfektionen der Vagina.The invention relates to a new pharmaceutical composition containing a combination of clindamycin and clotrimazole for vaginal use in bacterial infections, fungal or mixed infections of the vagina.

Herkömmliche Therapien zur Behandlung von bakteriellen vaginalen Infektionen, wie z.B. bakterielle Vaginose, die durch das Zusammenwirken von Gardnerella vaginalis und anaeroben Bakterien zustande kommen, sehen Behandlungen mit Chemotherapeutika mit Wirkung auf Anaerobier und Protozoen, wie z.B: Metronidazol oder Tinidazol oder aber die Behandlung mit einem Antibiotikum wie Amoxicillin oder Clindamycin vor. Die Behandlung erfolgt entweder oral oder durch lokale, vaginale Applikation.Conventional therapies for the treatment of bacterial vaginal infections, e.g. Bacterial vaginosis, which is caused by the interaction of Gardnerella vaginalis and anaerobic bacteria, provides treatments with chemotherapeutic agents with an effect on anaerobes and protozoa, such as: metronidazole or tinidazole, or treatment with an antibiotic such as amoxicillin or clindamycin. Treatment is either oral or by local vaginal application.

Die orale Therapie mit einem dieser Wirkstoffe besitzt erhebliche Nachteile, wie z.B. das Auftreten von erheblichen Nebenwirkungen oder aber auch unerwünschte Wechselwirkungen mit anderen Arzneimitteln. Zudem steht Metronidazol im Verdacht, kanzerogenes Potential zu haben. Eine Lokaltherapie ist auf jeden Fall einer systemischen Therapie vorzuziehen, um eine systemische Belastung des Körpers zu vermeiden.Oral therapy with one of these active substances has considerable disadvantages, e.g. the occurrence of significant side effects or undesirable interactions with other drugs. Metronidazole is also suspected to have carcinogenic potential. Local therapy is definitely preferable to systemic therapy to avoid systemic stress on the body.

Bisherige lokale Therapien mit Metronidazol sahen Dosierungen von 500 bis 1000 mg Metronidazol als Einmalgabe vor oder bei einer 5-Tage Therapie 200-500 mg Metronidazol pro Tag. Wird der Wirkstoff in einer halbfesten Zubereitung, wie z.B. als Gel oder Creme verabreicht, sind Gaben von ca. 100 mg pro Tag üblich. Analoge Mengen werden mit demPrevious local therapies with metronidazole saw doses of 500 to 1000 mg metronidazole as a single dose before or with 5-day therapy 200-500 mg metronidazole per day. If the active ingredient is in a semi-solid preparation, e.g. Administered as a gel or cream, doses of approximately 100 mg per day are common. Analog quantities are with the

BESTATIGUNGSKOPIE Wirkstoff Clindamycin angewandt. Jedoch werden auch bei der Lokaltherapie die gleichen oder ähnliche Nebenwirkungen beschrieben wie bei der oralen Anwendung der Wirkstoffe.CONFIRMATION COPY Active ingredient clindamycin applied. However, the same or similar side effects are described for local therapy as for oral use of the active ingredients.

Ein wesentlicher Nachteil der oben beschriebenen Therapien mit einem Antibiotikum oder einem Chemotherapeutikum ist, daß sowohl bei oraler als auch bei lokaler Therapie häufig eine sekundäre Infektion z. B. Vaginalcandidose oder eine Mischinfektion innerhalb des Folgemonats auftreten kann, wodurch eine erneute Behandlung mit einem weiteren Medikament erforderlich wird. Eine sehr genaue und aufwendige Diagnose ist dann notwendig, um festzustellen, welche Art einer Kolpitis vorliegt, damit medikamentös richtig behandelt werden kann.A major disadvantage of the above-described therapies with an antibiotic or a chemotherapeutic agent is that a secondary infection, e.g. B. vaginal candidiasis or a mixed infection can occur within the following month, which requires re-treatment with another drug. A very precise and time-consuming diagnosis is then necessary to determine what type of colpitis is present so that medication can be treated correctly.

Eine der wohl am häufigsten auftretende Folgeinfektion ist die Vaginalcandidose, eine Pilzinfektion, die eine Behandlung mit einem Antimykotikum, wie z.B. Clotrimazol erforderlich macht.One of the most common secondary infections is vaginal candidiasis, a fungal infection that requires treatment with an antifungal such as e.g. Clotrimazole required.

Clotrimazol ist ein Lokal-Antimykotikum mit einem breitem Wirkungsspektrum, das viele humanpathogene Pilze umfaßt. In der Gynäkologie wird Clotrimazol vorwiegend zur Behandlung von vulvovaginalen Infektionen durch Hefe- oder Sproßpilze als Monotherapie eingesetzt. Bei der lokalen Therapie mit Clotrimazol werden Dosierungen von 500 mg bei der Einmalapplikation vorgesehen. Mehrtägige Behandlungstherapien werden mit Dosierungen von ca. 100-200 mg Clotrimazol durchgeführt.Clotrimazole is a local antifungal drug with a broad spectrum of activity, which includes many human-pathogenic fungi. In gynecology, clotrimazole is primarily used as a monotherapy for the treatment of vulvovaginal infections caused by yeast or shoots. With local therapy with clotrimazole, doses of 500 mg are provided for single use. Treatment therapies lasting several days are carried out with doses of approx. 100-200 mg of clotrimazole.

Es ist des weiteren bekannt, daß neben der antimy kotischen Wirkung Clotrimazol eine geringe antibakterielle Wirkung besitzt.It is also known that in addition to the antimycotic effect, clotrimazole has a low antibacterial effect.

Aufgabe der Erfindung ist es, eine pharmazeutische Zusammensetzung zur Behandlung vaginaler Erkrankungen bereit zu stellen, bei der die Nebenwirkungen reduziert sind und mit der die Behandlung einfacher und effizienter wird.The object of the invention is to provide a pharmaceutical composition for the treatment of vaginal diseases in which the side effects are reduced and with which the treatment is simpler and more efficient.

Dies konnte durch eine neue pharmazeutische Zusammensetzung, die als aktive Bestandteile die Wirkstoffe Clindamycin und Clotrimazol enthält, erreicht werden.This was achieved through a new pharmaceutical composition that contains the active ingredients clindamycin and clotrimazole as active ingredients.

Dabei wurde überraschenderweise gefunden, daß geringere Dosierungen erforderlich sind, als bei der Behandlung mit den einzelnen Wirkstoffen. Die Kombination zeigt einen deutlichen synergistischen Effekt. Während nach dem Stand der Technik Clindamycin bei der Lokaltherapie in Dosismengen von 100-200 mg pro Tag zu verabreichen ist, um eine vollständige Ausheilung der Erkrankung zu erzielen, kann bei der neuen Kombination die Clindamycindosis auf 10-80 mg, vorzugsweise auf 20-50 mg reduziert werden. Je nach Schwere der Erkrankung werden Dosismengen von 10-80 mg, vorzugsweise von 20-50 mg Clindamycin in Kombination mit 50-150 mg, vorzugsweise mit 50-100 mg Clotrimazol verabreicht.It was surprisingly found that lower dosages are required than in the treatment with the individual active ingredients. The combination shows a clear one synergistic effect. While according to the prior art clindamycin is to be administered in local therapy in dose amounts of 100-200 mg per day in order to achieve complete healing of the disease, the clindamycin dose in the new combination can be reduced to 10-80 mg, preferably to 20-50 mg can be reduced. Depending on the severity of the disease, dose amounts of 10-80 mg, preferably 20-50 mg clindamycin in combination with 50-150 mg, preferably 50-100 mg clotrimazole are administered.

Vorzugsweise ist die neue pharmazeutische Zusammensetzung zur lokalen Verwendung bei der Behandlung von vaginalen Infektionen bestimmt.Preferably, the new pharmaceutical composition is for local use in the treatment of vaginal infections.

Die pharmazeutische Zusammensetzung kann neben den aktiven Bestandteilen pharmazeutische annehmbare Träger oder Hilfsstoffe enthalten. Bevorzugte Darreichungsformen sind Vaginalsuppositoria, Vaginaltabletten, Vaginalovula, Vaginalringe oder halbfeste Vaginalzubereitungen wie Salbe, Creme oder Gel.In addition to the active ingredients, the pharmaceutical composition can contain pharmaceutically acceptable carriers or excipients. Preferred dosage forms are vaginal suppositories, vaginal tablets, vaginal ovula, vaginal rings or semi-solid vaginal preparations such as ointment, cream or gel.

Unter üblichen Tablettenhilfsstoffen werden hier die nachstehenden verstanden: Stärke, z.B. Maisstärke, Reisstärke, Kartoffelstärke, Weizenstärke, Milchzucker (Lactose), Glucose, Saccharose, mikrokristalline Cellulose, Siliciumdioxid kollodial, Magnesiumstearat, Stearinsäure, Talcum, Polyvinylpyrrolidon (linear und quervernetzt), Natriumchlorid, Polyethylenglycol, Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Gelatine, Calciumphosphat, Cellulose, Mannit, Natriumcarboxymethylstärke, Natriumcarbonat, Natriumbicarbonat, Calciumcarbonat, Natriumcarboxymethylcellulose (linear und quervernetzt) und Magnesiumstearat.Common tablet excipients are understood here to mean the following: starch, e.g. Corn starch, rice starch, potato starch, wheat starch, milk sugar (lactose), glucose, sucrose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, stearic acid, talc, polyvinylpyrrolidone (linear and crosslinked), sodium chloride, polyethylene glycol, hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, hydroxypropylcellulose, cellulose Mannitol, sodium carboxymethyl starch, sodium carbonate, sodium bicarbonate, calcium carbonate, sodium carboxymethyl cellulose (linear and cross-linked) and magnesium stearate.

Weitere Tablettenhilfsstoffe siehe „Die Tablette, Grundlagen und Praxis des Tablettierens, Granulierens und Dragierens" von W.A. Ritschel, S.85-144, sowie „Katalog pharmazeutischer Hilfsstoffe" verfaßt von einer Arbeitsgruppe der Firma Ciba-Geigy, Hoffmann-La Röche und Sandoz, Basel 1974.For further tablet excipients see "The tablet, basics and practice of tableting, granulating and coating" from WA Ritschel, p.85-144, and "Catalog of pharmaceutical excipients" written by a working group from Ciba-Geigy, Hoffmann-La Röche and Sandoz, Basel 1974.

Unter üblichen Hilfsstoffen für Cremes werden hier die nachstehenden verstanden: Sorbitanmonostearat, Polysorbat 60, Cetylpalmitat, Paraffin, Cetylstearylalkohol, Benzylalkohol, Siliciumdioxid, Triacetin, Isopropylmonostearat, Polyethylenglycol, Glycerolmonostearat, Polyacrylsäure, Natriumhydroxid, Docusat-Natrium, Dimethicon, Triglyceride, Octyldecanol und Octyldodecanol.The usual auxiliaries for creams are understood here to mean the following: sorbitan monostearate, polysorbate 60, cetyl palmitate, paraffin, cetylstearyl alcohol, benzyl alcohol, silicon dioxide, triacetin, isopropyl monostearate, polyethylene glycol, Glycerol monostearate, polyacrylic acid, sodium hydroxide, docusate sodium, dimethicone, triglycerides, octyldecanol and octyldodecanol.

Unter üblichen Hilfsstoffen für Ovula werden hier die nachstehenden verstanden: Gelatine, Glycerol, Polyethylenglycol, Hartfett, Cetostearylalkoholpolyethylenglycolether, Natriumdodecylsulfat, Glycerol(mono,di,tri)fettsäureester(C 12-C 18)-Polyethylenglycol- dodecylether Gemisch, Paraffin, Ethyl-4-hydroxybenzoat, Propyl-4-hydroxybenzoat und Vaseline.The usual excipients for ovules are understood here to mean the following: gelatin, glycerol, polyethylene glycol, hard fat, cetostearyl alcohol polyethylene glycol ether, sodium dodecyl sulfate, glycerol (mono, di, tri) fatty acid ester (C 12 -C 18) polyethylene glycol dodecyl ether mixture, paraffin, ethyl 4 -hydroxybenzoate, propyl-4-hydroxybenzoate and petroleum jelly.

Die Vaginaltabletten können in Form von Einschicht-, Zweischicht- oder Dreischichttabletten oder als Tabletten mit Brausesatz vorliegen.The vaginal tablets can be in the form of single-layer, two-layer or three-layer tablets or as tablets with effervescent.

Die aktiven Bestandteile der neuen Zusammensetzung liegen in Konzentrationen von 10-80 mg Clindamycin und 50-150 mg Clotrimazol, vorzugsweise 20-50 mg Clindamycin und 50- 100 mg Clotrimazol, insbesondere in 20 mg Clindamycin und 100 mg Clotrimazol pro Anwendung bzw. Dosiseinheit vor.The active components of the new composition are present in concentrations of 10-80 mg clindamycin and 50-150 mg clotrimazole, preferably 20-50 mg clindamycin and 50-100 mg clotrimazole, in particular in 20 mg clindamycin and 100 mg clotrimazole per application or dose unit .

Die neue Kombination kann zur Behandlung einer Vielzahl von vaginalen Erkrankungen eingesetzt werden. So können die am häufigsten auftretende Kolpitiden, die Candida-Kolpitis (Pilzinfektion) und die bakterielle Vaginose ( bakterielle Mischinfektion) erfolgreich behandelt werden.The new combination can be used to treat a wide range of vaginal diseases. The most common colpitids, candida colpitis (fungal infection) and bacterial vaginosis (mixed bacterial infection) can be successfully treated.

Des weiteren erlaubt die erfindungsgemäße Kombination die Behandlung sogenannter Mischinfektionen, die durch Bakterien und Pilze hervorgerufen werden. Bei der Applikation der erfindungsgemäßen Kombination werden gleichzeitig beide Krankheitserreger bekämpft.Furthermore, the combination according to the invention allows the treatment of so-called mixed infections caused by bacteria and fungi. When the combination according to the invention is applied, both pathogens are combated simultaneously.

Unklare Infektionen erfordern üblicherweise äußerst aufwendige diagnostische Bestimmungen. Bei der Behandlung solcher Erkrankungen mit der Kombination aus Clindamycin und Clotrimazol reduziert sich dieser Aufwand erheblich, da es praktisch unerheblich ist, welche Art der Kolpitis vorliegt.Unclear infections usually require extremely complex diagnostic tests. When treating such diseases with the combination of clindamycin and clotrimazole, this effort is considerably reduced, since it is practically irrelevant what type of colpitis is present.

Bei der Monotherapie einer Infektion mit einem Antibiotikum nach dem Stand der Technik ist die am häufigsten auftretende Sekundärinfektion eine Candidose. Mit dem Einsatz der erfindungsgemäßen Kombination bei der Behandlung lassen sich solche Sekundärinfektionen verhindern. Dadurch erübrigt sich eine weitere Behandlung, die zum einen für den Patienten sehr unerfreulich und mit einer verlängerten Behandlungsdauer verbunden ist und zum anderen kann durch die Kombinationstherapie vom gesundheitspolitischen Standpunkt der finanzielle Aufwand deutlich verringert werden.When monotherapy for a prior art antibiotic infection, the most common secondary infection is candidiasis. With the use of the Combination according to the invention in the treatment can prevent such secondary infections. This eliminates the need for further treatment, which on the one hand is very unpleasant for the patient and is associated with an extended treatment duration, and on the other hand, the combination therapy can significantly reduce the financial outlay from a health policy point of view.

Die Erfindung wird durch nachstehende Beispiele näher erläutert, ohne aber den Erfindungsumfang damit einzuschränken.The invention is illustrated in more detail by the following examples, but without restricting the scope of the invention.

Beispiel 1:Example 1:

EinschichttabletteSingle-layer tablet

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin-HCL (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg

Lactose D20 265,0 mgLactose D20 265.0 mg

Maisstärke 33,3 mgCorn starch 33.3 mg

Hydroxypropylcellulose (HPC) (Klucel EF) 2,0 mgHydroxypropyl cellulose (HPC) (Klucel EF) 2.0 mg

Calciumlactat x 5 H2O 30,0 mgCalcium lactate x 5 H 2 O 30.0 mg

Milchsäure 41,0 mgLactic acid 41.0 mg

Mikrokristalline Cellulose (Avicel PH 102) 128,0 mgMicrocrystalline cellulose (Avicel PH 102) 128.0 mg

Kollidon CL 12,0 mgKollidon CL 12.0 mg

Aerosil 200 7,0 mgAerosil 200 7.0 mg

Magnesiumstearat 7,0 mgMagnesium stearate 7.0 mg

Clotrimazol, Clindamycin-HCl, Lactose, ein Teil der Maisstärke, HPC, Calciumlactat und Milchsäure werden in einem Wirbelschichtgranulator granuliert. Das erhaltene Granulat sowie der restliche Teil der Maisstärke, Kollidon, mikrokristalline Cellulose, Magnesiumstearat und Aerosil werden durch ein Zwangssieb (1,25 mm) gegeben und in einem Containermischer homogenisiert. Die erhaltene Mischung wird auf einer Rundlauftablettenmaschine zu Tabletten verpreßt. Beispiel 2:Clotrimazole, clindamycin HCl, lactose, part of the corn starch, HPC, calcium lactate and lactic acid are granulated in a fluidized bed granulator. The granules obtained and the remaining part of the corn starch, Kollidon, microcrystalline cellulose, magnesium stearate and Aerosil are passed through a forced sieve (1.25 mm) and homogenized in a container mixer. The mixture obtained is compressed to tablets on a rotary tablet machine. Example 2:

Einschichttablette :Single-layer tablet:

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin-HCL (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg

Lactose D20 265,0 mgLactose D20 265.0 mg

Maisstärke 33,3 mgCorn starch 33.3 mg

HPC (Klucel EF) 2,0 mgHPC (Klucel EF) 2.0 mg

Calciumlactat x 5 H2O 90,0 mgCalcium lactate x 5 H 2 O 90.0 mg

Milchsäure 35,0 mgLactic acid 35.0 mg

Mikrokristalline Cellulose (Avicel PH 102) 128,0 mgMicrocrystalline cellulose (Avicel PH 102) 128.0 mg

Kollidon CL 12,0 mgKollidon CL 12.0 mg

Aerosil 200 7,0 mgAerosil 200 7.0 mg

Magnesiumstearat 7,0 mgMagnesium stearate 7.0 mg

Mit den vorstehend angegebenen Bestandteilen wird eine Tablette in Analogie zu Beispiel 1 hergestellt.A tablet is produced in analogy to Example 1 with the ingredients specified above.

Beispiel 3:Example 3:

Einschichttablette :Single-layer tablet:

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin-HCL (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg

Lactose D20 795,3 mgLactose D20 795.3 mg

Maisstärke 100,0 mgCorn starch 100.0 mg

HPC (Klucel EF) 5,0 mgHPC (Klucel EF) 5.0 mg

Calciumlactat x 5 H2O 30,0 mgCalcium lactate x 5 H 2 O 30.0 mg

Milchsäure 70,0 mgLactic acid 70.0 mg

Mikrokristalline Cellulose (Avicel PH 102) 384,5 mgMicrocrystalline cellulose (Avicel PH 102) 384.5 mg

Kollidon CL 35,0 mg Aerosil 200 23,0 mgKollidon CL 35.0 mg Aerosil 200 23.0 mg

Magnesiumstearat 22,5 mgMagnesium stearate 22.5 mg

Clotrimazol, Clindamycin-HCl, Lactose, ein Teil der Maisstärke, ein Teil der mikrokristallinen Cellulose, HPC, Calciumlactat und Milchsäure werden in einem Wirbelschichtgranulator granuliert. Das erhaltene Granulat sowie der restliche Teil der Maisstärke und der mikrokristallinen Cellulose, Kollidon, Magnesiumstearat und Aerosil werden durch ein Zwangssieb (1,25 mm) gegeben und in einem Containermischer homogenisiert. Die erhaltene Mischung wird auf einer Rundlauftablettenmaschine zu Tabletten verpreßt.Clotrimazole, clindamycin HCl, lactose, part of the corn starch, part of the microcrystalline cellulose, HPC, calcium lactate and lactic acid are granulated in a fluidized bed granulator. The granules obtained and the remaining part of the corn starch and the microcrystalline cellulose, Kollidon, magnesium stearate and Aerosil are passed through a forced sieve (1.25 mm) and homogenized in a container mixer. The mixture obtained is compressed to tablets on a rotary tablet machine.

Beispiel 4:Example 4:

Zweischichttablette:Two-layer tablet:

1. Schicht 2. Schicht1st layer 2nd layer

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin-HCL (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg

Lactose D20 265,0 mg 265,0 mgLactose D20 265.0 mg 265.0 mg

Maisstärke 33,0 mg 33,6 mgCorn starch 33.0 mg 33.6 mg

HPC (Klucel EF) 2,0 mg 2,0 mgHPC (Klucel EF) 2.0 mg 2.0 mg

Calciumlactat x 5 H2O 90,0 mg 10,0 mgCalcium lactate x 5 H 2 O 90.0 mg 10.0 mg

Milchsäure 35,0 mg 23,0 mgLactic acid 35.0 mg 23.0 mg

Mikrokristalline Cellulose (Avicel PH 102) 128,0 mg 128,0 mgMicrocrystalline cellulose (Avicel PH 102) 128.0 mg 128.0 mg

Kollidon CL 12,0 mg 12,0 mgKollidon CL 12.0 mg 12.0 mg

Aerosil 200 7,0 mg 7,7 mgAerosil 200 7.0 mg 7.7 mg

Magnesiumstearat 7,0 mg 7,0 mgMagnesium stearate 7.0 mg 7.0 mg

Mit den oben genannten Bestandteilen wird zum einen ein Granulat für die erste Schicht und zum anderen ein Granulat für die zweite Schicht analog Beispiel 1 hergestellt und zu einer Zweischichttablette verpreßt. Beispiel 5:On the one hand, the above-mentioned constituents are used to produce granules for the first layer and, on the other hand, granules for the second layer analogously to Example 1 and pressed into a two-layer tablet. Example 5:

Zweischichttablette:Two-layer tablet:

1. Schicht 2. Schicht1st layer 2nd layer

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin-HCL (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg

Lactose D20 265,0 mg 265,0 mgLactose D20 265.0 mg 265.0 mg

Maisstärke 33,0 mg 33,6 mgCorn starch 33.0 mg 33.6 mg

HPC (Klucel EF) 2,0 mg 2,0 mgHPC (Klucel EF) 2.0 mg 2.0 mg

Calciumlactat x 5 H2O 90,0 mgCalcium lactate x 5 H 2 O 90.0 mg

Milchsäure 35,0 mgLactic acid 35.0 mg

Mikrokristalline Cellulose (Avicel PH 102) 128,0 mg 128,0 mgMicrocrystalline cellulose (Avicel PH 102) 128.0 mg 128.0 mg

Kollidon CL 12,0 mg 12,0 mgKollidon CL 12.0 mg 12.0 mg

Aerosil 200 7,0 mg 7,7 mgAerosil 200 7.0 mg 7.7 mg

Magnesiumstearat 7,0 mg 7,0 mgMagnesium stearate 7.0 mg 7.0 mg

Mit den vorstehend angegebenen Bestandteilen wird eine Tablette in Analogie zu Beispiel 4 hergestellt.A tablet is produced in analogy to Example 4 with the ingredients specified above.

Beispiel 6:Example 6:

Einschichttablette :Single-layer tablet:

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin-HCL (entspricht 10 mg Clindamycin) 11,4 mgClindamycin HCL (equivalent to 10 mg clindamycin) 11.4 mg

Lactose D20 265,0 mgLactose D20 265.0 mg

Maisstärke 33,6 mgCorn starch 33.6 mg

HPC (Klucel EF) 2,0 mgHPC (Klucel EF) 2.0 mg

Calciumlactat x 5 H2O 90,0 mgCalcium lactate x 5 H 2 O 90.0 mg

Milchsäure 35,0 mgLactic acid 35.0 mg

Mikrokristalline Cellulose (Avicel PH 102) 128,0 mg Kollidon CL 12,0 mgMicrocrystalline cellulose (Avicel PH 102) 128.0 mg Kollidon CL 12.0 mg

Aerosil 200 7,0 mgAerosil 200 7.0 mg

Mit den vorstehend angegebenen Bestandteilen wird eine Tablette in Analogie zu Beispiel 1 hergestellt.A tablet is produced in analogy to Example 1 with the ingredients specified above.

Beispiel 7:Example 7:

Zweischichttablette:Two-layer tablet:

1. Schicht 2. Schicht1st layer 2nd layer

1 ^^l 1Uvt"t*ιiπni 'TffU 1l 150,0 mg1 ^^ l 1Uvt "t * ιiπni 'TffU 1l 150.0 mg

Clindamycin-HCL (entspricht 30 mg Clindamycin) 34,1 mgClindamycin HCL (equivalent to 30 mg clindamycin) 34.1 mg

Lactose D20 280,0 mg 280,0 mgLactose D20 280.0 mg 280.0 mg

Maisstärke 40,0 mg 38,9 mgCorn starch 40.0 mg 38.9 mg

HPC (Klucel EF) 3,0 mg 3,0 mgHPC (Klucel EF) 3.0 mg 3.0 mg

Calciumlactat x 5 H2O 100,0 mgCalcium lactate x 5 H 2 O 100.0 mg

Milchsäure 40,0 mgLactic acid 40.0 mg

Mikrokristalline Cellulose (Avicel PH 102) 140,0 mg 135,0 mgMicrocrystalline cellulose (Avicel PH 102) 140.0 mg 135.0 mg

Kollidon CL 15,0 mg 15,0 mgKollidon CL 15.0 mg 15.0 mg

Aerosil 200 9,0 mg 9,0 mgAerosil 200 9.0 mg 9.0 mg

Magnesiumstearat 9,0 mg 9,0 mgMagnesium stearate 9.0 mg 9.0 mg

Mit den vorstehend angegebenen Bestandteilen wird eine Tablette in Analogie zu Beispiel 4 hergestellt. Beispiel 8:A tablet is produced in analogy to Example 4 with the ingredients specified above. Example 8:

Dreischichttablette:Three-layer tablet:

1. Schicht 3. Schicht1st layer 3rd layer

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin-HCL (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg

Lactose D20 265,0 mg 265,0 mgLactose D20 265.0 mg 265.0 mg

Maisstärke 33,0 mg 33,6 mgCorn starch 33.0 mg 33.6 mg

HPC (Klucel EF) 2,0 mg 2,0 mgHPC (Klucel EF) 2.0 mg 2.0 mg

Calciumlactat x 5 H2O 90,0 mgCalcium lactate x 5 H 2 O 90.0 mg

Milchsäure 35,0 mgLactic acid 35.0 mg

Mikrokristalline Cellulose (Avicel PH 102) 128,0 mg 128,0 mgMicrocrystalline cellulose (Avicel PH 102) 128.0 mg 128.0 mg

Kollidon CL 12,0 mg 12,0 mgKollidon CL 12.0 mg 12.0 mg

Aerosil 200 7,0 mg 7,7 mgAerosil 200 7.0 mg 7.7 mg

Magnesiumstearat 7,0 mg 7,0 mgMagnesium stearate 7.0 mg 7.0 mg

Die zweite Schicht stellt eine Zwischenschicht dar, die sich zwischen der ersten und dritten Schicht befindet.The second layer represents an intermediate layer which is located between the first and third layers.

Zwischenschicht:Interlayer:

Lactose (Tablettose) 58,7 mg Avicel PH 102 30,0 mg Aerosil 0,5 mgLactose 58.7 mg Avicel PH 102 30.0 mg Aerosil 0.5 mg

Magnesiumstearat 0,8 mg Maisstärke 10,0 mg Beispiel 9:Magnesium stearate 0.8 mg corn starch 10.0 mg Example 9:

Zweischichttablette:Two-layer tablet:

1. Schicht 2. Schicht1st layer 2nd layer

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin-HCL (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg

Lactose D20 265,0 mg 93,7 mgLactose D20 265.0 mg 93.7 mg

Maisstärke 33,0 mg 20,0 mgCorn starch 33.0 mg 20.0 mg

HPC (Klucel EF) 2,0 mgHPC (Klucel EF) 2.0 mg

Calciumlactat x 5 H2O 90,0 mgCalcium lactate x 5 H 2 O 90.0 mg

Milchsäure 35,0 mgLactic acid 35.0 mg

Mikrokristalline Cellulose (Avicel PH 102) 128,0 mg 60,0 mgMicrocrystalline cellulose (Avicel PH 102) 128.0 mg 60.0 mg

Kollidon CL 12,0 mgKollidon CL 12.0 mg

Aerosil 200 7,0 mg 1,6 mgAerosil 200 7.0 mg 1.6 mg

Magnesiumstearat 7,0 mg 2,0 mgMagnesium stearate 7.0 mg 2.0 mg

Mit den vorstehend angegebenen Bestandteilen wird die erste Schicht in Analogie zu Beispiel 1 granuliert. Die clindamycinhaltige Schicht wird nicht granuliert, sondern direkt mit dem Granulat der ersten Schicht zu einer Zweischichttablette verpreßt.The first layer is granulated analogously to Example 1 with the constituents specified above. The clindamycin-containing layer is not granulated, but is pressed directly with the granulate of the first layer into a two-layer tablet.

Beispiel 10;Example 10;

Tablette mit Brausesatz (Einschicht):Tablet with effervescent set (single layer):

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin-HCL (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCL (equivalent to 20 mg clindamycin) 22.7 mg

Lactose D20 265,0 mgLactose D20 265.0 mg

Maisstärke 33,3 mgCorn starch 33.3 mg

HPC (Klucel EF) 2,0 mgHPC (Klucel EF) 2.0 mg

Calciumlactat x 5 H2O 90,0 mgCalcium lactate x 5 H 2 O 90.0 mg

Milchsäure 35,0 mgLactic acid 35.0 mg

Mikrokristalline Cellulose (Avicel PH 102) 120,0 mg Citronensäure 50,0 mgMicrocrystalline cellulose (Avicel PH 102) 120.0 mg Citric acid 50.0 mg

Adipinsäure 10,0 mgAdipic acid 10.0 mg

Aerosil 200 7,0 mgAerosil 200 7.0 mg

Magnesiumstearat 7,0 mgMagnesium stearate 7.0 mg

Natriumhydrogencarbonat 30,0 mgSodium bicarbonate 30.0 mg

Clotrimazol, Clindamycin-HCl, Lactose, Maisstärke, HPC, Calciumlactat und Milchsäure werden in einem Wirbelschichtgranulator granuliert.Clotrimazole, clindamycin HCl, lactose, corn starch, HPC, calcium lactate and lactic acid are granulated in a fluidized bed granulator.

Das erhaltene Granulat wird mit den übrigen Brause- und/ oder Zerfallskomponenten sowie mit mikrokristalliner Cellulose, Magnesiumstearat und Aerosil gemischt und zu Tabletten verpreßt.The granules obtained are mixed with the other effervescent and / or disintegrating components, as well as with microcrystalline cellulose, magnesium stearate and Aerosil, and compressed into tablets.

Beispiel 11:Example 11:

Vaginalcreme:Vaginal cream:

Eine Appliziereinheit beträgt 5 Gramm. Diese enthält 100 mg Clotrimazol und 20 mg Clindamycin.One application unit is 5 grams. This contains 100 mg clotrimazole and 20 mg clindamycin.

Ein Gramm Creme ist entsprechend zusammengesetzt:One gram of cream is composed accordingly:

Clotrimazol 20,0 mgClotrimazole 20.0 mg

Clindamycin-HCl (entspricht 4 mg Clindamycin) 4,54 mgClindamycin HCl (equivalent to 4 mg clindamycin) 4.54 mg

Sorbitanmonostearat 20,0 mgSorbitan monostearate 20.0 mg

Polysorbat 60 (Tween 60) 15,0 mgPolysorbate 60 (Tween 60) 15.0 mg

Cetylpalmitat (Cutina CP-A) 30,0 mgCetyl palmitate (Cutina CP-A) 30.0 mg

Dickflüssiges Paraffin 130,46 mgViscous paraffin 130.46 mg

Cetylstearylalkohol 100,0 mgCetylstearyl alcohol 100.0 mg

Benzylalkohol 10,0 mgBenzyl alcohol 10.0 mg

Gereinigtes Wasser 670,0 mg Beispiel 12:Purified water 670.0 mg Example 12:

Ovulum (100/20):Ovulum (100/20):

Pro Ovulum werden folgende Bestandteile zusammengefügt:The following components are put together for each ovule:

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin- HCI (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCI (equivalent to 20 mg clindamycin) 22.7 mg

Calciumlactat x 5H2O 77,3 mgCalcium lactate x 5H 2 O 77.3 mg

Gelantine 250,0 mgGelantine 250.0 mg

Gereinigtes Wasser 250,0 mgPurified water 250.0 mg

Glycerol 1250,0 mgGlycerol 1250.0 mg

Beispiel 13:Example 13:

Ovulum (100/20):Ovulum (100/20):

Pro Ovulum werden folgende Bestandteile zusammengefügt:The following components are put together for each ovule:

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin- HCI (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCI (equivalent to 20 mg clindamycin) 22.7 mg

Calciumlactat x 5H2O 77,3 mgCalcium lactate x 5H 2 O 77.3 mg

Macrogol 400 1000,0 mgMacrogol 400 1000.0 mg

Macrogol 6000 800,0 mgMacrogol 6000 800.0 mg

Milchsäure 200,0 mg Lactic acid 200.0 mg

Beispiel 14:Example 14:

Ovulum/ SuppositoriumOvulum / suppository

Pro Ovulum werden folgende Bestandteile zusammengefügt:The following components are put together for each ovule:

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin- HCI (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCI (equivalent to 20 mg clindamycin) 22.7 mg

Calciumlactat x 5H2O 77,3 mgCalcium lactate x 5H 2 O 77.3 mg

Hartfett 1800,0 mgHard fat 1800.0 mg

Beispiel 15:Example 15:

Ovulum (100/20):Ovulum (100/20):

Pro Ovulum werden folgende Bestandteile zusammengefügt:The following components are put together for each ovule:

Clotrimazol 100,0 mgClotrimazole 100.0 mg

Clindamycin- HCI (entspricht 20 mg Clindamycin) 22,7 mgClindamycin HCI (equivalent to 20 mg clindamycin) 22.7 mg

Calciumlactat x 5H2O 77,3 mgCalcium lactate x 5H 2 O 77.3 mg

Hartfett 1780,0 mgHard fat 1780.0 mg

Cetomacrogol 1000 20,0 mgCetomacrogol 1000 20.0 mg

Beispiel 16:Example 16:

Die erfindungsgemäße pharmazeutische Zusammensetzung wurde in einer Studie bei 25 Patientinnen angewandt. Bei diesen 25 Patientinnen wurde in 20 Fällen eine bakterielle Mischinfektion, in 3 Fällen eine Mischinfektion, hervorgerufen durch Bakterien und Pilze und in 2 Fällen eine reine Pilzinfektion festgestellt.The pharmaceutical composition according to the invention was used in a study in 25 patients. In these 25 patients a bacterial mixed infection was found in 20 cases, in 3 cases a mixed infection caused by bacteria and fungi and in 2 cases a pure fungal infection.

Nach einer 6-tägigen Therapie frisch zubereiteten Vaginalovula, die 20 mg Clindamycin und 100 mg Clotrimazol enthielten, wurde bei 23 Patientinnen eine vollständige Ausheilung der Infektion erzielt. Es konnten des weiteren keine Sekundärinfektionen festgestellt werden. After a 6-day therapy of freshly prepared vaginal ovula, which contained 20 mg clindamycin and 100 mg clotrimazole, the infection was completely healed in 23 patients. Furthermore, no secondary infections were found.

Claims

Patentansprüche claims 1. Pharmazeutische Zusammensetzung enthaltend als aktive Bestandteile Clindamycin und Clotrimazol und mindestens einen pharmazeutisch annehmbaren Träger dafür.1. Pharmaceutical composition containing clindamycin and clotrimazole as active ingredients and at least one pharmaceutically acceptable carrier therefor. 2. Pharmazeutische Zusammensetzung nach Anspruch 1 zur Verwendung bei der Behandlung von vaginalen Infektionen.2. A pharmaceutical composition according to claim 1 for use in the treatment of vaginal infections. 3. Pharmazeutische Zusammensetzung nach Anspruch 1 oder 2 bei welcher die Formulierung für eine vaginale Verabreichung adaptiert ist.3. A pharmaceutical composition according to claim 1 or 2, wherein the formulation is adapted for vaginal administration. 4. Pharmazeutische Zusammensetzung nach einem der vorhergehenden Ansprüche, worin die Mengen an aktiven Bestandteilen 10 bis 80 mg Clindamycin und 50 bis 150 mg Clotrimazol pro Applikationseinheit, vorzugsweise 20 bis 50 mg Clindamycin und 50 bis 100 mg Clotrimazol pro Applikationseinheit, insbesondere 20 mg Clindamycin und 100 mg Clotrimazol pro Applikationseinheit betragen.4. Pharmaceutical composition according to one of the preceding claims, wherein the amounts of active ingredients 10 to 80 mg clindamycin and 50 to 150 mg clotrimazole per application unit, preferably 20 to 50 mg clindamycin and 50 to 100 mg clotrimazole per application unit, in particular 20 mg clindamycin and 100 mg clotrimazole per application unit. 5. Pharmazeutische Zusammensetzung nach einem der vorhergehenden Ansprüche in Form einer Einschichttablette, Brausetablette, Zweischichttablette, Dreischichttablette, Vaginalring, Suppositorium oder Ovulum zur vaginalen Applikation.5. Pharmaceutical composition according to one of the preceding claims in the form of a single-layer tablet, effervescent tablet, two-layer tablet, three-layer tablet, vaginal ring, suppository or ovule for vaginal application. 6. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 4 in Form einer halbfesten Formulierung. 6. Pharmaceutical composition according to one of claims 1 to 4 in the form of a semi-solid formulation. 7. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 1 bis 6, bei dem man die aktiven Bestandteile Clindamycin und Clotrimazol mit mindestens einem pharmazeutisch annehmbaren Träger vereinigt. 7. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 6, in which the active ingredients clindamycin and clotrimazole are combined with at least one pharmaceutically acceptable carrier.
PCT/EP1998/005454 1997-08-27 1998-08-27 Pharmaceutical composition containing clindamycin and clotrimazol for treating vaginal infections WO1999009964A2 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
DE59813162T DE59813162D1 (en) 1997-08-27 1998-08-27 PHARMACEUTICAL COMPOSITION CONTAINING CLINDAMYCIN AND CLOTRIMAZOLE, FOR THE TREATMENT OF VAGINAL INFECTIONS
JP2000507355A JP2001513550A (en) 1997-08-27 1998-08-27 New pharmaceutical composition
US09/486,348 US6537970B1 (en) 1997-08-27 1998-08-27 Pharmaceutical composition
EP98948878A EP1009414B1 (en) 1997-08-27 1998-08-27 Novel pharmaceutical composition comprising clindamycin and clotrimazol for the treatment of vaginal infections
AU95343/98A AU9534398A (en) 1997-08-27 1998-08-27 Novel pharmaceutical composition
AT98948878T ATE308328T1 (en) 1997-08-27 1998-08-27 PHARMACEUTICAL COMPOSITION CONTAINING CLINDAMYCIN AND CLOTRIMAZOLE, FOR THE TREATMENT OF VAGINAL INFECTIONS

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19737348.8 1997-08-27
DE19737348A DE19737348C2 (en) 1997-08-27 1997-08-27 Pharmaceutical composition containing clindamycin and clotrimazole

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EP (1) EP1009414B1 (en)
JP (1) JP2001513550A (en)
AT (1) ATE308328T1 (en)
AU (1) AU9534398A (en)
DE (2) DE19737348C2 (en)
WO (1) WO1999009964A2 (en)

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JP2003519095A (en) * 1999-08-06 2003-06-17 ファルマシア・アンド・アップジョン・カンパニー Vaginal clindamycin oval composition
US8709482B2 (en) 2004-08-05 2014-04-29 Ferring B.V. Stabilised prostaglandin composition
US9987364B2 (en) 2002-09-27 2018-06-05 Ferring B.V. Water-swellable polymers
US10105445B2 (en) 2006-07-05 2018-10-23 Ferring B.V. Hydrophilic polyurethane compositions

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EP1421093B1 (en) * 2001-08-28 2005-06-29 Pharmacia Corporation Crystaline clindamycin free base
MXPA05006505A (en) * 2002-12-18 2005-09-30 Ferrer Int Pharmaceutical compositions of sertaconazole for vaginal use.
MXPA05008571A (en) * 2005-08-12 2007-02-12 Leopoldo Espinosa Abdala Pharmaceutical formulations in the form of solids, semisolids, in suspension, in solution, in emulsion or in syrup, containing clindamycin and one or more members of the azole family.
GB0613638D0 (en) 2006-07-08 2006-08-16 Controlled Therapeutics Sct Polyurethane elastomers
CN101500583B (en) * 2006-07-12 2012-05-23 控制治疗（苏格兰）有限公司 Drug delivery polymers containing clindamycin hydrochloride
GB0620685D0 (en) * 2006-10-18 2006-11-29 Controlled Therapeutics Sct Bioresorbable polymers
US8603513B2 (en) * 2007-06-28 2013-12-10 The Procter & Gamble Company Article comprising calcium for reducing the production of TSST-1
EP2130531A1 (en) * 2008-06-04 2009-12-09 Rolf Kullgren AB Vaginal suppository comprising lactic acid
US20100285096A1 (en) * 2009-05-05 2010-11-11 Fancheng Wang Hygiene Article Having Calcium Sugar Phosphate
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WO2011027247A1 (en) 2009-09-03 2011-03-10 Sulur Subramaniam Vanangamudi An antifungal cream comprising terbinafine hydrochloride
WO2011101826A1 (en) 2010-02-22 2011-08-25 Sulur Subramaniam Vanangamudi A medicinal fusidic acid cream made using sodium fusidate and incorporating a biopolymer, terbinafine and dexamethasone, and a process to make it
WO2012049542A1 (en) 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi A medicinal fusidic acid cream made using sodium fusidate and incorporating a biopolymer, mometasone as a corticosteroid and clotrimazol as antifungal agent, and a process to make it
WO2012049544A1 (en) 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi A medicinal fusidic acid cream made using sodium fusidate and incorporating a biopolymer, a hydrocortisone acetate as a corticosteroid, and clotrimazole as an antifungal agent, and a process to make it
CN103830198B (en) * 2012-11-28 2016-05-18 南京亿华药业有限公司 A kind of Mycoporin vaginal sheet and preparation method thereof

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US4318853A (en) 1980-01-31 1982-03-09 The Upjohn Company 9β,11β-Epoxy-5β-corticoids
US5160737A (en) * 1988-05-03 1992-11-03 Perio Products Ltd. Liquid polymer composition, and method of use

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003519095A (en) * 1999-08-06 2003-06-17 ファルマシア・アンド・アップジョン・カンパニー Vaginal clindamycin oval composition
US9987364B2 (en) 2002-09-27 2018-06-05 Ferring B.V. Water-swellable polymers
US8709482B2 (en) 2004-08-05 2014-04-29 Ferring B.V. Stabilised prostaglandin composition
US10105445B2 (en) 2006-07-05 2018-10-23 Ferring B.V. Hydrophilic polyurethane compositions

Also Published As

Publication number Publication date
AU9534398A (en) 1999-03-16
EP1009414A2 (en) 2000-06-21
DE19737348A1 (en) 1999-03-04
ATE308328T1 (en) 2005-11-15
JP2001513550A (en) 2001-09-04
DE59813162D1 (en) 2005-12-08
US6537970B1 (en) 2003-03-25
DE19737348C2 (en) 2002-07-25
WO1999009964A3 (en) 1999-06-10
EP1009414B1 (en) 2005-11-02

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